Project Summary/Abstract Age-related macular degeneration (AMD) is the leading cause of severe vision loss and legal blindness in persons over age 50 in the United States. In its advanced stages, patients lose vision from either choroidal neovascularization or geographic atrophy. Although great progress has been made during the past decade in the treatment of neovascular AMD, currently no therapy exists to slow or reverse the dry or non-neovascular form, in which drusen (deposits consisting of lipid and protein) accumulate beneath key cells in the central portion of the macula, leading to further dysfunction that can predispose to the complications of advanced disease, with reduced visual acuity and central scotomata. Dry AMD generally progresses inexorably such that drusen volume increases each year, with increasing risk of these complications and worse vision. Metformin is a generic oral medication used for its hypoglycemic effects but which also has been found to have numerous other cellular actions, including reducing oxidative stress and reactive oxygen species production, inflammation, and mitochondrial stress -- all processes central to the pathogenesis of AMD. Notably, the drug has been found to have myriad anti-senescence effects and has recently been tested extensively for anti-aging endpoints in non-diabetic patients. The current study proposes to determine whether metformin can reduce the progression of drusen accumulation in AMD. Non-diabetic patients enrolled in the study will be randomized to either placebo or daily oral metformin. Over the course of 24 months, the two groups will be compared by several measures. In Aim 1, AMD will be assessed with multimodal imaging, including optical coherence tomography, fundus autofluorescence, and fundus photography. The cube root of the drusen volume at baseline versus 18 and 24 months will be the primary outcome measure for assessing the effect of oral metformin; incidence of new choroidal neovascularization and geographic atrophy will also be compared. In Aim 2, best-corrected Early Treatment of Diabetic Retinopathy Study visual acuity and other visual psychophysical tests will be compared between the two groups. This will identify effects on visual performance independent of anatomic changes in drusen. In Aim 3, subjective visual function, as it relates to quality of life, will be assessed using the National Eye Institute Visual Function Questionnaire and the Low Luminance Questionnaire. This measure is particularly relevant in patients with AMD, as the disease dramatically impacts patients' quality of life for the worse. The current planning grant will enable preparations for a clinical trial that can evaluate this inexpensive medication for the treatment of AMD. Therefore, the present high-reward study has the potential to enable a cost-effective treatment that could be rapidly adopted worldwide to prevent vision loss and blindness.